scholarly journals Role of mTOR Signaling in Tumor Microenvironment: An Overview

2018 ◽  
Vol 19 (8) ◽  
pp. 2453 ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Italia Falcone ◽  
Sara Pilotto ◽  
Emilio Bria ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
New Combination ◽  
Combination Therapies ◽  
Cellular Processes ◽  
Promising Target ◽  
Exogenous Cues

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.

scholarly journals The Role of mTOR Signaling as a Therapeutic Target in Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1743
Author(s):  
Nadezhda V. Popova ◽  
Manfred Jücker
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Cell Processes ◽  
And Function ◽  
Available Information ◽  
Mtor Complex 1

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

scholarly journals Small Extracellular Vesicles in the Development, Diagnosis, and Possible Therapeutic Application of Esophageal Squamous Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zheng Zhao ◽  
Shuyue Yang ◽  
Anni Zhou ◽  
Xiao Li ◽  
Rui Fang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Extracellular Vesicle ◽  
Early Diagnostics ◽  
Therapeutic Application ◽  
Promising Target

Esophageal squamous cell carcinoma (ESCC) persists among the most lethal and broad-spreading malignancies in China. The exosome is a kind of extracellular vesicle (EV) from about 30 to 200 nm in diameter, contributing to the transfer of specific functional molecules, such as metabolites, proteins, lipids, and nucleic acids. The paramount role of exosomes in the formation and development of ESCC, which relies on promoting intercellular communication in the tumor microenvironment (TME), is manifested with immense amounts. Tumor-derived exosomes (TDEs) participate in most hallmarks of ESCC, including tumorigenesis, invasion, angiogenesis, immunologic escape, metastasis, radioresistance, and chemoresistance. Published reports have delineated that exosome-encapsulated cargos like miRNAs may have utility in the diagnosis, as prognostic biomarkers, and in the treatment of ESCC. This review summarizes the function of exosomes in the neoplasia, progression, and metastasis of ESCC, which improves our understanding of the etiology and pathogenesis of ESCC, and presents a promising target for early diagnostics in ESCC. However, recent studies of exosomes in the treatment of ESCC are sparse. Thus, we introduce the advances in exosome-based methods and indicate the possible applications for ESCC therapy in the future.

scholarly journals Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy

2019 ◽  
Vol 20 (9) ◽  
pp. 2241 ◽  
Author(s):  
Debarati Banik ◽  
Sara Moufarrij ◽  
Alejandro Villagra
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Critical Role ◽  
Preclinical Studies ◽  
Clinical Use ◽  
Combination Therapies ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Fda Approval

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

scholarly journals mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

2020 ◽  
Vol 21 (8) ◽  
pp. 2718 ◽  
Author(s):  
Yasmine Lund-Ricard ◽  
Patrick Cormier ◽  
Julia Morales ◽  
Agnès Boutet
Keyword(s):  
Evolutionary Biology ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Human Diseases ◽  
Whole Body ◽  
Body Parts ◽  
Animal Kingdom ◽  
Structure Damage ◽  
Wide Range

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

scholarly journals Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

2020 ◽  
Vol 21 (9) ◽  
pp. 3285 ◽  
Author(s):  
Choudhary Harsha ◽  
Kishore Banik ◽  
Hui Li Ang ◽  
Sosmitha Girisa ◽  
Rajesh Vikkurthi ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Therapeutic Interventions ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Mesenchymal Transition

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 43-43
Author(s):  
Da Wang ◽  
Roland Chiu ◽  
John Theodorus Plukker ◽  
Robert P. Coppes
Keyword(s):  
Esophageal Cancer ◽  
Cell Lines ◽  
Mammalian Target Of Rapamycin ◽  
Neoadjuvant Chemoradiotherapy ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Biopsy ◽  
Sphere Formation ◽  
Dose Dependent

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.

scholarly journals The Role of AMPK/mTOR Signaling Pathway in Anticancer Activity of Metformin

2021 ◽  
pp. 501-508
Author(s):  
Nikola Chomanicova ◽  
Andrea Gazova ◽  
Adriana Adamickova ◽  
Simona Valaskova ◽  
Jan Kyselovic
Keyword(s):  
Anticancer Activity ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Mtor Pathway ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Treatment Of Diabetes

Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF’s mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.

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